Myeloid derived suppressor cells (MDSC) are a diverse population of immature granulocytic and monocytic cells that infiltrate human and murine tumors and exacerbate disease. A growing body of evidence including our preliminary findings in both mouse and human tumors suggests that it is the more proinflammatory tumors that can aggressively promote their own progression by activating cytokines that enhance MDSC expansion, their recruitment to tumor, and their increased expression of angiogenic and immunosuppressive effector molecules. We find that both the granulocytic-(G) and monocytic-(M) MDSC populations are heterogenous with respect to chemokine receptor expression where distinct subsets are highly enriched for expression of immunosuppressive and/or angiogenic molecules, rendering them potentially important therapeutic targets. This is particularly true for G-MDSC- and M-MDSC subpopulations expressing CXCR2 either alone or in conjunction with other chemokine receptors. This abundance of immunosuppressive- and angiogenic G-MDSCs that infiltrate inflammatory murine tumors is paralleled in human renal cell carcinoma (RCC) tumors, which also accumulate mostly G-MDSCs. He we propose that inflammation promotes tumor progression through multiple pathways including induction of immunosuppressive and pro-angiogenic gene expression programs within the CXCR2 populations in the BM, modulation of the CXCR2 chemokine/chemokine receptor axes that control the trafficking of MDSCs from the bone marrow to the tumor, and regulation of the phenotype and functional activity of the CXCR2+ MDSCs after their arrival within the tumor tissue. We propose three specific aims to test our hypothesis using several animal tumor models (Renca, SIRCC, 4T1, B16 and CT26) along with blood and tumor samples from patients with renal cell carcinoma (RCC). Here we will: 1) Identify the cytokines responsible for the accumulation of CXCR2+ MDSC with tumor promoting activity. 2) Define the role of the CXCR2/chemokine receptor axis as being integral for eliciting the most angiogenic, immunosuppressive and disease-promoting MDSC subpopulations to tumors. 3) Assess the impact that the tumor microenvironment has in shaping the immunosuppressive and proangiogenic gene expression profile of infiltrating MDSC subsets. The findings from these studies should identify CXCR2+ G-MDSC and to a lesser extent M-MDSC as critical populations important in promoting immune suppression and angiogenesis in certain inflammatory tumors such as human RCC. Defining the chemokine and cytokines involved in promoting the dominance of CXCR2+ MDSC may lead to new therapeutic targets.